national academy of sciences

George Constantin Cotzias

1918—1977

A Biographical Memoir by
Vincent P. Dole

Any opinions expressed in this memoir are those of the author(s)

and do not necessarily reflect the views of the
National Academy of Sciences.

Biographical Memoir

Copyright 1995
National Academies Press
washington d.c.
 G E O R G E C O N S TA N T I N C O T Z I A S
June 16, 1918–June 13, 1977

BY VINCENT P. DOLE

G EORGE CONSTANTIN COTZIAS was born in the city of Chania

on the island of Crete, the eldest child of Constantin
and Catherine Stroumboli Cotzias and the grandson of
George J. Cotzias, a wealthy merchant in Athens. His father,
Constantin George Cotzias, a lawyer and journalist, had re-
cently been banished from Athens because of political ac-
tivity in support of the king. He was arrested by the fascist
government of Eleftherios Venizelos and exiled to Crete to
limit his political influence, but he was able to return to
Athens eighteen months later. Soon after returning he es-
tablished an influential newspaper and an advertising agency.
Twelve years later, in 1932, he became president of the
Greek chamber of commerce and in 1934 was elected mayor
of Athens.
As mayor and later in the expanded role of governmen-
tal minister for all municipal activities in the region of Greater
Athens, Constantin Cotzias shaped the political structure of
the modern city of Athens. He reorganized its government,
initiated programs of health and public works, rebuilt the
municipal hospital, paved roads, created parks, supported
young artists, and established a new municipal symphony
orchestra.

63
64 BIOGRAPHICAL MEMOIRS

This productive period was terminated abruptly by the

invasion of Greece in 1940. After an intense but brief resis-
tance, the Greek armies were defeated. The prime minister,
Alexandros Koryzis, refusing to acknowledge defeat and
collaborate, committed suicide. In this extremity, King George
of Greece asked Constantin Cotzias to go to the United
States as ambassador-at-large representing the Greek gov-
ernment in exile.
George and his family arrived in New York in August
1941, financially destitute after a desperate four-month jour-
ney through warring countries. They remained in New York
until the defeat of the Axis powers in 1945 made it possible
for his parents to return. To complete this account,
Constantin Cotzias was reelected mayor of Athens by an
over whelming majority in the first postwar election (1951),
but he died shortly afterwards of a heart attack at the age
of fifty-nine while resuming his municipal duties. Cotzias
Square, next to the town hall of the city of Athens, bears
his name.
As the eldest son of a leading citizen of Athens prior to
these events, George Cotzias had a privileged early life, at-
tending the best schools and associating with the most stimu-
lating intellectuals of the city. Reflecting George’s mother’s
interest in literature, the Cotzias home was a meeting place
for leading writers of prewar Athens and, of course, as the
mayor’s residence, it was at the epicenter of public policy.
At the age of twenty-two, within one year of graduating
from medical school, George apparently was on his way to
an uneventful career as a medical practitioner in Athens,
specializing in surgery. He had become an assistant to the
professor of surger y, Xenophon Kondiades. However, the
invasion of Greece changed all plans. George immediately
volunteered for military service, although as a medical stu-
 GEORGE CONSTANTIN COTZIAS 65

dent he was exempt from the draft. At the request of Pro-

fessor Kondiades, heading a surgical team at a hospital close
to the Albanian front, he was assigned to this unit, but
while he was in transit the hospital was obliterated by bomb-
ing, which killed the entire staff. Military resistance col-
lapsed before the advancing German army. George made
his way back to Athens, rejoined his family, and left Greece
with them.
After arriving in New York in 1942, George applied for
admission to medical school to complete his studies. The
rejection by Cornell was unequivocal; not only was he found
to be deficient in English, he was told that his education in
Athens had provided inadequate training in basic biochem-
istry, pharmacology, and physiology. He would need fur-
ther premedical training even to be eligible for admission
to the first year of medical school. Applications to Colum-
bia, New York University, Johns Hopkins, and Pennsylvania
were equally fruitless.
Reminiscing in later years, George recalled critical advice
that his father gave him at this low point. “When I ran for
the office of councilman, I was defeated. So I ran for mayor
and was elected. Choose the leading medical school in the
countr y and apply there.” With this advice George applied
to Harvard Medical School and had the good fortune to be
interviewed by Soma Weiss, a brilliant professor of medi-
cine and himself a refugee a decade earlier from Nazi op-
pression. After a long conversation in German, which George
spoke fluently, Weiss recommended that he be admitted
conditionally to the third year of study at the medical school.
Two years later he graduated from Harvard cum laude. He
then trained as an intern in pathology at Brigham Hospital,
as an intern in medicine at Massachusetts General Hospi-
tal, and was a resident in neurology at Massachusetts Gen-
eral Hospital.
66 BIOGRAPHICAL MEMOIRS

This brings the story to the point at which I first knew

George Cotzias. During the four years of World War II, it
was my good fortune to be assigned to a naval medical
research unit based at the hospital of Rockefeller Institute
(now Rockefeller University) and to work in the depart-
ment of D. D. Van Slyke. With the end of the war and
demobilization, I left Rockefeller and returned to Massa-
chusetts General Hospital, where five years earlier I had
trained in medicine. Shortly afterward to my great surprise
and delight, the director of the Rockefeller Hospital, Tho-
mas Rivers, invited me to return to Rockefeller. He asked
me to form a new department, replacing that of Van Slyke,
who planned to move to Brookhaven National Laboratory
the following year.
My first act was to invite Lewis Dahl to join me; Dahl, a
scholarly physician and friend, who was completing a tour
as senior medical resident at Massachusetts General Hospi-
tal, agreed. Within the hour George burst into my office
and announced explosively, “I’m coming, too.” This unusual
application could have been counterproductive, but fortu-
nately Dahl had worked with Cotzias and gave him an en-
thusiastic endorsement. Immediately I had two talented as-
sociates with whom to start the department, the only difficulty
being there was no space for the new laboratory immedi-
ately available at Rockefeller. At Rivers’s suggestion, my two
associates were assigned to Van Slyke’s group during his
final year (an invaluable experience for them), and I started
my new career as department head with a year’s sabbatical
in Europe.
The five years after my return were busy ones. We stud-
ied hypertensive patients, looking for clues to the nature of
this disorder in disturbances of salt metabolism and energy
balance. George, in addition to loyal work as a team mem-
ber in the clinical studies, became interested in the me-
 GEORGE CONSTANTIN COTZIAS 67

tabolism of amines in the tissues. He reasoned that cat-

echolamines, diamines, and histamine have powerful vaso-
motor effects that might be relevant to hypertensive disor-
ders. In particular, he directed his attention to the enzymes
that limit their biological activity by oxidizing them.
George thus initiated studies that led him some fifteen
years later to the demonstration that l-DOPA (the amino
acid l-dihydroxy phenylalanine) was effective in giving symp-
tomatic relief to patients with disabling Parkinsonism. The
most important of these studies were conducted after he
left my department in 1954. Dahl left at the same time,
both having outgrown the limited opportunities for advance-
ment at Rockefeller. They transferred their work to
Brookhaven National Laboratory, where Van Slyke mean-
while had established a strong medical division and was
able to provide space and support for each to develop an
active, independent laboratory.
The move to Brookhaven also provided George with a
new resource for metabolic studies, namely a cyclotron. When
activated by a beam of high-energy neutrons, trace metals
in samples of tissue and blood can be determined with un-
precedented sensitivity and specificity. George seized the
opportunity. In a series of basic studies over the following
decade, he elucidated the distribution, absorption, elimina-
tion kinetics, and probable function of manganese. At the
same time he became interested in its toxicity, manifest
especially in the neurological symptoms of Chilean miners
excavating manganese ore. As a neurologist he was impressed
by the similarity of the symptoms to those of classical
Parkinson’s disease (rigidity, retardation of motion, trem-
ors, lack of coordination), and as a pathologist he was at-
tracted by the opportunity to correlate specific structural
lesions made by a known toxin to disturbances of brain
function. In both disorders the main lesions found in the
68 BIOGRAPHICAL MEMOIRS

brain involve the substantia nigra, a region made conspicu-

ous by a deposit of dark melanin pigment. It was known
that this region of the brain is rich in the neurotransmitter
dopamine and also that both melanin and dopamine are
derived from common precursors. Further, it was known
that this region is deficient in both substances in patients
with Parkinson’s disease.
A possible remedy, as was evident to several investigators
at the time, is to increase the supply of dopamine to the
neurones in this region. However, dopamine administered
as a medication (orally or by injection) cannot reach the
site in significant concentration because it does not pass
the blood-brain barrier. As an alternative, one can look for
precursors of dopamine that are not excluded by the bar-
rier, administer them in large doses, and hope that when
the molecules arrive at the critical site enough will be con-
verted into dopamine to have a therapeutic effect. Other
investigators had pursued this idea with little success, al-
though the validity of the approach was shown by the tran-
sient benefit seen after injection of the precursor, dihydroxy-
phenylalanine (DOPA). But this effect was only of theoretical
interest. It was not of practical value as a treatment because
of the severe toxicity associated with the injection.
Cotzias, at this point, made a critical observation that
converted the transient response into a successful, large-
scale treatment. By starting with very small doses of DOPA,
given orally every two hours under continued observation,
and gradually increasing the dose over a period of several
weeks as permitted by the development of tolerance, he
was able to stabilize patients on large enough doses to cause
a dramatic remission of their symptoms. He further im-
proved the treatment by utilizing the active isomer, l-DOPA,
recognizing that the inactive isomer, d-DOPA (which con-
stitutes 50 percent of the dose in a racemic mixture) is
 GEORGE CONSTANTIN COTZIAS 69

responsible for 50 percent of the toxicity but contributes

nothing to the therapeutic result.
The result was soon confirmed by other investigators and
has now become the standard treatment for Parkinsonian
symptoms. To his credit, Cotzias realized that this success
was only one step toward a definitive treatment. After hav-
ing a remission, many patients show a disturbing tendency
to relapse, even with continued treatment, or to develop
movement disorders. He therefore was engaged during the
last decade of his life in testing supplementary treatments,
especially those utilizing structural analogs of dopamine (like
apomorphine) that could penetrate the blood-brain barrier
and substitute for dopamine without having to be converted
by local enzymes. By a remarkable coincidence, his early
interest in the function of bioactive amines in tissues and
his subsequent investigations of the toxicity of manganese
converged on this problem. Cotzias was at work on the de-
velopment of new medications when his career was termi-
nated by lung cancer. Like his father, he died at age fifty-
nine, before his work was finished.
George was a large man physically and intellectually—
restless, fiercely loyal, informed, intuitive, quick in conver-
sation with an infectious laugh that began as a furtive chuckle
and grew into a roar. Basically he remained the intense
young medical resident who burst into my office in 1946
announcing, “I’m coming, too.” He is survived by his widow,
Betty, and a son, Constantin George Cotzias.
Among the honors and awards received by George Cotzias
were election to the National Academy of Sciences (1973),
election to the American Academy of Arts and Sciences
(1970), the A. Cressy Morrison Award in Natural Sciences
(1954), the Albert Lasker Award in Clinical Medical Re-
search (1969), the Borden Award of the Association of Ameri-
can Medical Colleges (1972), and the annual award of the
70 BIOGRAPHICAL MEMOIRS

American College of Physicians (1974). He received honor-

ar y degrees from Catholic University, Santiago (1969);
Women’s Medical College of Pennsylvania (1970); St. John’s
University, New York (1971); and the National University,
Athens (1974).
 GEORGE CONSTANTIN COTZIAS 71

SELECTED BIBLIOGRAPHY

1947
With W. H. Sweet, J. Seed, and P. Yakovlev. Gastrointestinal hemor-
rhages, hyperglycemia, azotemia, hyperchloremia and hypermatremia
following lesions of the frontal lobe in man. In The Frontal Lobes,
ed. J. F. Fulton, C. D. Aring, and S. B. Wortis, vol. 27, pp. 795-
822. Baltimore: Williams & Wilkins.
With G. I. Lavin and D. D. Van Slyke. Observations on normal and
pathologic kidney tissue with ultraviolet photomicrography. Acta
Med. Scand. (Suppl.) 196:259.

1949
With J. H. Baxter. Effects of proteinuria on the kidney. Proteinuria,
renal enlargement and renal injury consequent on protracted
parenteral administration of protein solution in rats. J. Exp. Med.
89:643-67.

1950
With V. P. Dole, L. K. Dahl, H. A. Eder, and M. E. Krebs. Dietary
treatment of hypertension. Clinical and metabolic studies of pa-
tients on the rice-fruit diet. J. Clin. Invest. 29:1189-1206.

1951
With V. P. Dole, L. K. Dahl, D. D. Dziewiatkowski, and C. Harris.
Dietary treatment of hypertension. II. Sodium depletion as re-
lated to the therapeutic effect. J. Clin. Invest. 30:584-95.
With V. P. Dole. A nomogram for the calculation of relative cen-
trifugal force. Science 113:552-53.
With V. P. Dole. Metabolism of amines. I. Microdetermination of
monoamine oxidase in tissues. J. Biol. Chem. 190:665-72.
With V. P. Dole. Metabolism of amines. II. Mitochondrial localiza-
tion of monoamine oxidase. Proc. Soc. Exp. Biol. Med. 78:157-60.

1952
With V. P. Dole. The activity of histaminase in tissues. J. Biol. Chem.
196:235-42.
Monoamine oxidase: substrates and inhibitors. In Transactions of the
72 BIOGRAPHICAL MEMOIRS

Second Conference on Shock and Circulatory Homeostasis, ed. H. D.

Green. New York: Josiah Macy, Jr., Foundation.

1953
With V. P. Dole, L. K. Dahl, I. L. Schwartz, J. H. Thaysen, and C.
Harris. Dietary treatment of hypertension. III. The effects of pro-
tein on appetite and weight. J. Clin. Invest. 32:185-91.

1954
With L. K. Dahl and B. G. Stall III. Metabolic effects of marked
sodium restriction on hypertensive patients; changes in the total
exchangeable sodium and potassium. J. Clin. Invest. 33:1397-1406.
With H. A. Eder, H. D. Lauson, F. P. Chinard, R. Greif, and D. D.
Van Slyke. A study of the mechanisms of edema formation in
patients with the nephrotic syndrome. J. Clin. Invest. 33:636-56.
With I. Serlin and J. J. Greenough. Preparation of soluble monoam-
ine oxidase. Science 120:144-45.

1955
With L. S. Maynard. The partition of manganese among organs and
intracellular organelles of the rat. J. Biol. Chem. 214:489-95.
With I. Serlin. Microdiffusion of acetic acid as an assay for acetyl-
cholinesterase. J. Biol. Chem. 215:263-68.
With L. S. Maynard. The study of certain phases of cell dynamic
states with short lived isotopes as exemplified by Mn56 partition
studies in organs and intracellular organelles. In Proceedings of the
International Conference on Peaceful Uses of Atomic Energy, vol 12, pp.
444-46. Geneva: United Nations.
With L. K. Dahl and B. G. Stall. Metabolic effects of marked sodium
restriction in hypertensive patients. Skin electrolyte losses. J. Clin.
Invest. 34:462-70.

1957
With I. Serlin. State of tissue acetylcholinesterase as determined by
Cobalt 60 gamma radiation inactivation. Radiat. Res. 6:55-66.

1958
With J. J. Greenough. Concomitant analysis for oxygen uptake and
 GEORGE CONSTANTIN COTZIAS 73
ammonia evolution during the monoamine oxidase reaction. Arch.
Biochem. Biophys. 75:15-23.
With J. J. Greenough. Specificity of the manganese pathway through
the body. J. Clin. Invest. 37:1298-1305.
With D. C. Borg. Manganese metabolism in man: rapid exchange of
Mn 56 with tissue as demonstrated by blood clearance and liver
uptake. J. Clin. Invest. 37:1269-78.
Manganese in health and disease. Physiol. Rev. 38:503-32.
With A. J. Bertinchamps. Dosimetry of radioisotopes. Science 128:988-
90.
With D. C. Borg. Incorporation of manganese into erythrocytes as
evidence for a manganese porphyrin in man. Nature 182:1677-78.

1959
With A. J. Bertinchamps and J. J. Greenough. Thirst for bile in rats
with bile fistulas. Nature 184:1405.
With J. J. Greenough. Quantitative estimation of amineoxidase. Na-
ture 183:1732-33.
Diagnostic uses of radioisotopes. Symposium and panel discussion
on the uses of radioisotopes in clinical practice. NY State J. Med.
59:18.

1960
With J. J. Greenough. Dependence of periodic activation and inhi-
bition of monoaminoxidase by aliphatic compounds upon chain-
length. Nature 185:384-85.
Metabolic relations of manganese to other minerals. Symposium on
Interactions of Mineral Elements in Nutrition and Metabolism.
Fed. Proc. 19:655-58.
With D. C. Borg and A. J. Bertinchamps. Clinical experience with
manganese. In Metal-Binding in Medicine, ed. M. J. Seven and L.
A. Johnson, pp. 50-58. Philadelphia: Lippincott.
1961
Manganese versus magnesium: Why are they so similar in vitro and
so different in vivo? Fed. Proc. pt. II, suppl. 10, 20:98-103.
With P. S. Papavasiliou. Neutron activation analysis: the determina-
tion of manganese. J. Biol. Chem. 236:2365-69.
74 BIOGRAPHICAL MEMOIRS

With D. C. Borg and B. Selleck. Specificity of the zinc pathway in

the rabbit: zinc-cadmium exchange. Am. J. Physiol. 201:63-66.
With D. C. Borg and B. Selleck. Virtual absence of turnover in
cadmium metabolism: Cd109 studies in the mouse. Am. J. Physiol.
201:927-30.
With D. C. Borg, A. J. Bertinchamps, E. R. Hughes, and P. S. Papavasiliou.
Nuclear studies in medicine: manganese metabolism. In Sympo-
sium Nuklear under Klinike (with special reference to cancer and
cardiovascular diseases) Wissenschaftliche abhandlungen der
arbeitsgemeinschaft fur forschung des landes nordrheinwestfalen,
ed. L. E. Farr, et al., vol 18, pp. 49-58. Koln: Westdeuchen Verlag.
With D. C. Borg, E. R. Hughes, A. J. Bertinchamps, and P. S. Papavasiliou.
Phenothiazine: curative or causative in regard to Parkinsonism?
In Symposium on the Extrapyramidal System and Neuroleptics, ed. J-M.
Bordeleau, vol. 20, pp. 193-98. Montreal: University of Montreal.
With E. R. Hughes. Adrenocorticosteroid hormones and manga-
nese metabolism. Am. J. Physiol. 201:1061-64.
1962
With G. C. Borg and B. Selleck. Specificity of the zinc pathway
through the body: the turnover of Zn 65 in the mouse. Am. J.
Physiol. 202:359-63.
With E. R. Hughes and E. P. Cronkite. Total body irradiation and
manganese metabolism. Nature 193:792-95.
With D. C. Borg. Interaction of trace metals with phenothiazine
drug derivatives. I. Structure-reactivity correlations. II. Forma-
tion of free radicals. III. Theoretical part. Proc. Natl. Acad. Sci.
U.S.A. 48:617-42.
With P. S. Papavasiliou. State of binding of natural manganese in
human cerebrospinal fluid, blood and plasma. Nature 195:823-24.
Manganese. In Mineral Metabolism: An Advanced Treatise, ed. C. L.
Comar and F. Bronner, vol. II, pt. B, pp. 403-42. New York: Aca-
demic Press.
With D. C. Borg. Phenothiazines and manganese. In Ultrastructure
and Metabolism of the Nervous System, ed. S. R. Korey, A. Pope, and
E. Robins, vol. XL, p. 337. Baltimore: Williams & Wilkins.

1963
With P. S. Papavasiliou and S. T. Miller. Neutron activation analysis:
 GEORGE CONSTANTIN COTZIAS 75
clinical and biological studies of manganese. In Third Colloque
International de Biologie de Saclay, pp. 287-306.

1964
Trace metals: essential or detrimental to life? Brookhaven Lecture
Series, vol. 26, pp. 1-14.
With M. H. Van Woert. Manganese poisoning—new insights. Lima,
Peru. Oct. 1963. Revista de Neuro-Psiquiatria, pp. 392-404.
With P. S. Papavasiliou. Primordial homeostasis in a mammal as
shown by the control of manganese. Nature 201:828-29.
With B. M. Patten, A. Sakamoto, M. H. Van Woert, and P. S. Papavasiliou.
Tremorine induced tremor versus extrapyramidal disease. Nature
201:929-30.
With P. S. Papavasiliou and S. T. Miller. Manganese in melanin.
Nature 201:1228-29.
With P. S. Papavasiliou. The specificity of the zinc pathway through
the body: homeostatic considerations. Am. J. Physiol. 206:787-92.
With P. S. Papavasiliou, M. H. Van Woert, and A. Sakamoto. Mel-
anogenesis and extrapyramidal diseases. Fed. Proc. 23:713-18.
Der Manganmetabolismus und seine Storungen. Verhandlungen der
Deutschen Gesellschaft fur innere Medizin, 70:327-30. German
Society of Internal Medicine, Wiesbaden.
Transport, homeostasis and specificity in trace metal metabolism.
In Proceedings of the Sixth International Congress of Nutrition, pp.
252-69. Edinburgh: E. & S. Livingstone.

1965
With K. N. Prasad and H. A. Johnson. A cytoplasmic organelle of
melanocytes. Nature 205:525-26.
With K. N. Prasad. A nomogram for the estimation of microcuries
and millimicrograms from cpm. J. Nucl. Med. 6:297-99.
With E. Homsher. Antidiuretic hormone and bile flow. Nature 208:687-
88.
With M. H. Van Woert. Possible roles of melanin in some extrapyra-
midal functions. In Monographs Biology and Medicine, p. 95. New
York: Grunne & Stratton.
With M. H. Van Woert and A. R. Nicholson. Functional similarities
between the cytoplasmic organelles of melanocytes and the mito-
chondria of hepatocytes. Nature 208:810-11.
76 BIOGRAPHICAL MEMOIRS

1966
Manganese, melanins and the extrapyramidal system. J. Neurosurg.
24:170-80.
With M. H. Van Woert. Anion inhibition of monoamine oxidase.
Biochem. Pharmacol. 15:275-85.
With S. T. Miller and J. Edwards. Neutron activation analysis: the
stability of manganese concentrations in human blood and plasma.
J. Lab. Clin. Med. 67:836-49.
With A. A. Britton. Dependence of manganese turnover on intake.
Am. J. Physiol. 211:203-6.
With E. R. Hughes and S. T. Miller. Tissue concentrations of man-
ganese and adrenal function. Am. J. Physiol. 211:207-10.
With P. S. Papavasiliou and S. T. Miller. Role of the liver in regulat-
ing distribution and excretion of manganese. Am. J. Physiol. 211:211-
16.
With A. J. Bertinchamps and S. T. Miller. Interdependence of routes
excreting manganese. Am. J. Physiol. 211:217-24.

1967
Manganese in biological system. In Encyclopedia of Biochemistry, ed.
R. J. Williams and E. M. Lansford, Jr., p. 506. New York: Reinhold.
With M. H. Van Woert and L. Schiffer. Aromatic amino acids and
modification of Parkinsonism. N. Engl. J. Med. 276:374-79.
With I. Mena, O. Marin, and S. Fuenzalida. Chronic manganese
poisoning: clinical picture and manganese turnover. Neurology 17:128-
36.
With M. H. Van Woert and A. Nicholson. Mitochondrial functions
of polymelanosomes. Comp. Biochem. Physiol. 22:477-85.
With A. C. Foradori, A. Bertinchamps, and J. M. Gulibon. The dis-
crimination between magnesium and manganese by serum pro-
teins. J. Gen. Physiol. 50:2255.
Importance of trace substance in environmental health as exempli-
fied by manganese. Paper presented at the First Annual Confer-
ence on Trace Substances in Environmental Health, University
of Missouri, Columbia.
Dopa and Parkinsonism (Letter to the Editor) Br. Med. J. 3:497.
With P. S. Papavasiliou. Therapeutic studies of Parkinsonian pa-
tients: long-term effects of D-L and L-dopa. In Progress in Neuro-
 GEORGE CONSTANTIN COTZIAS 77
Genetics, ed. A. Barbeau, and J-R. Brunette, pp. 357-65. Amsterdam:
Excerpta Medica Foundation.

1968
With P. S. Papavasiliou, E. R. Hughes, L. Tang, and D. C. Borg.
Slow turnover of manganese in active rheumatoid arthritis accel-
erated by prednisone. J. Clin. Invest. 47:992-1001.
With K. Horiuchi, S. Fuenzalida, and I. Mena. Chronic manganese
poisoning: clearance of tissue manganese burdens with persis-
tence of the neurological picture. Neurology 18:376-82.
With A. C. Foradori. Trace metal metabolism. In The Biological Basis
of Medicine, ed. E. E. and N. Bittar, vol. 1, chap. 3, pp. 105-21.
New York: Academic Press.
L-dopa for Parkinsonism. N. Engl. J. Med. 278-630.
With P. S. Papavasiliou, R. Gellene, and R. B. Aronson. Parkinsonism
and dopa. Trans. Assoc. Am. Physicians 81:171-83.
With P. S. Papavasiliou and S. T. Miller. Functional interactions
between biogenic amines, 3′, 5′-cyclic AMP and manganese. Na-
ture 220:74-75.
Dihydroxyphenylalanine treatment of Parkinsonism. JAMA 205:129.

1969
With P. S. Papavasiliou, R. Gellene, R. B. Aronson, and I. Mena.
Long-term effects of dopa on Parkinsonism: a proposal. In Third
Symposium on Parkinson’s Disease, ed. F. G. Gillingham and I. M. L.
Donaldson, pp. 178-81. Edinburgh: E. & S. Livingstone.
With P. S. Papavasiliou and R. Gellene. Modification of Parkinsonism:
dyskinesias accompanying treatment with dopa. In Psychotropic Drugs
and Dysfunctions of Basal Ganglia: A Multidisciplinary Workshop, Public
Health Series Publication 1938, ed. G. E. Crane and R. Gardner,
Jr., pp. 140-47. Washington, D.C.: U.S. Government Printing Of-
fice.
With P. S. Papavasiliou and R. Gellene. Modification of Parkinsonism:
chronic treatment with L-dopa. N. Engl. J. Med. 280:337-45.
With P. S. Papavasiliou. Autoimmunity in patients treated with L-
dopa. JAMA 207:1353-54.
L-dopa (L-DOPA) treatment of Parkinsonism. JAMA 207:1522.
Parkinsonism and dopa: an editorial. J. Chronic Dis. 22:297-301.
With I. Mena, K. Horiuchi, and K. Burke. Chronic manganese poi-
78 BIOGRAPHICAL MEMOIRS

soning: individual susceptibility and absorption of iron. Neurology

19:1000-6
With P. S. Papavasiliou, R. Gellene, C. Fehling, and I. Mena. L-dopa
in the treatment of Parkinson’s syndrome and of chronic manga-
nese poisoning. In Proceedings of the Eighth International Congress of
Gerontology, vol. I.
With P. S. Papavasiliou and R. Gellene. L-dopa in Parkinson’s syn-
drome. N. Engl. J. Med. 281:272.
Metabolic modification of some neurologic disorders. JAMA 210:1255-
62.
2-amino-4-hydroxy-6-7-dimethyletrahydropteridine in Parkinson’s disease.
JAMA 210:1594.

1970
Limiting factors in the treatment with dopa. In L-dopa and Parkinsonism,
ed. A. Barbeau and F. H. McDowell, pp. 3-5. Philadelphia; F. A.
Davis.
With I. Mena, J. Court, S. Fuenzalida, and P. S. Papavasiliou. Modi-
fication of chronic manganese poisoning: treatment with L-dopa
or 5-OH tryptophan. N. Engl. J. Med. 282:5-10.
With P. S. Papavasiliou, C. Fehling, B. Kaufman, and I. Mena. Simi-
larities between neurological effects of L-dopa and of apomorphine.
N. Engl. J. Med. 282:31-33.
Catecholamines in the brain. N. Engl. J. Med. 282:513.
With S. Duby, J. Z. Ginos, A. Steck, and P. S. Papavasiliou. Dopam-
ine analogues for studies of Parkinsonism. N. Engl. J. Med. 283:1289.

1971
Levodopa in the treatment of Parkinsonism. The George R. Minot
Memorial Lecture, Chicago, Ill., June 22, 1970, JAMA 218:1903-8.
With P. S. Papavasiliou, A. Steck, and S. Duby. Parkinsonism and
levodopa. Clin. Pharmacol. Ther. 12:319-22.
With P. S. Papavasiliou, J. Z. Ginos, A. Steck, and S. Duby. Meta-
bolic modification of Parkinson’s disease and of chronic manga-
nese poisoning. Ann. Rev. Med. 22:305-26.
With L. Tang, J. Z. Ginos, A. R. Nicholson, and P. S. Papavasiliou.
Block of cerebral actions of L-dopa with methyl-receptor sub-
stances. Nature 231:533-34.
 GEORGE CONSTANTIN COTZIAS 79
With P. S. Papavasiliou. Blocking the negative effects of vitamin B6
on patients receiving L-dopa. JAMA 215:1504-5.
With L. C. Tank, S. T. Miller, and J. Z. Ginos. Melatonin and abnor-
mal movements induced by L-dopa in mice. Science 173:450-52.
With I. Mena and J. Court. Levodopa, involuntary movements and
fusaric acid. JAMA 218:1829-30.
L-dopa and prognosis. In Developments in Treatment for Parkinson’s
Disease, ed. G. C. Cotzias and F. H. McDowell, pp. 78-84. New
York: Medcom Press.
With S. E. Duby, A. J. Steck, and P. S. Papavasiliou. Apomorphine
versus L-dopa in Parkinsonism. Fed. Proc. 30:126.
With S. E. Duby and L. K. Dahl. Coupling of hypotensive and anti-
Parkinson effects with two dopaminergic drugs. Trans. Assoc. Am.
Physicians 84:289-96.

1972
With P. S. Papavasiliou, S. E. Duby, A. J. Steck, C. Fehling, and M.
A. Bell. Levodopa in parkinsonism: potentiation of central ef-
fects with a peripheral inhibitor. N. Engl. J. Med. 286:8-14.
Levodopa-orally or intravenously; negative pyridoxine effect. JAMA
219:226.
With W. H. Lawrence, P. S. Papavasiliou, S. E. Duby, J. Z. Ginos,
and I. Mena. Apomorphine and Parkinsonism. Trans. Am. Neurol.
Assoc. 97:156-59.
With J. Z. Ginos, A. LoMonte, and S. Wolf. Apomorphine: its dopam-
inergic action and its spectrofluorimetric determination. Fed. Proc.
31:269, 312.
With L. C. Tang, S. T. Miller, D. Sladic-Simic, and L. S. Hurley. A
mutation influencing the transportation of manganese, levodopa
and tryptophan. Science 176:410-12.
With P. S. Papavasiliou, S. E. Duby, A. J. Steck, and J. Z. Ginos.
Some newer metabolic concepts in the treatment of Parkinsonism.
Neurology 22(Suppl.):82-85.
With P. S. Papavasiliou, S. E. Duby, A. J. Steck, M. Bell, and W. H.
Lawrence. Melatonin and Parkinsonism. JAMA 221:88-89.
With L. C. Tank and I. Mena. Effects of inhibitors and stimulators
of protein synthesis on the cerebral actions of levodopa. In Chemical
Approaches to Brain Function, Neurosciences Research, ed. S. Ehrenpreis
and I. J. Kopin, vol. 5, pp. 97-108. New York: Academic Press.
80 BIOGRAPHICAL MEMOIRS

With S. E. Duby, P. S. Papavasiliou, and W. H. Lawrence. Injected

apomorphine and orally administered levodopa in Parkinsonism.
Arch. Neurol. 27:474-80.
With W. H. Lawrence, P. S. Papavasiliou, and S. E. Duby. Nicotina-
mide ineffective in Parkinsonism. N. Engl. J. Med. 287:147.
Limitations of controlled double-blind studies of drugs. N. Engl. J.
Med. 287:937.
Metabolic responses to levodopa. N. Engl. J. Med. 287:1302-3.

1973
With P. S. Papavasiliou and I. Mena. L-meta-tyrosine and Parkinsonism.
JAMA 223:83.
With N. G. Gillespie, I. Mena, and M. A. Bell. Diets affecting treat-
ment of Parkinsonism with levodopa. J. Am. Diet. Assoc. 62:525-28.
Levodopa and related drugs. Medical Letter 15:21-24.
With P. S. Papavasiliou and W. H. Lawrence. Levodopa and dopam-
ine in cerebrospinal fluid. Neurology 23:756-59.
With J. Z. Ginos, A. LoMonte, A. K. Bose, and R. J. Brambilla.
Synthesis of tritium- and deuterium-labeled apomorphine. J. Am.
Chem. Soc. 95:2991-94.
With I. Mena and P. S. Papavasiliou. Overview of present treatment
of Parkinsonism with Levodopa. Adv. Neurol. 2:265-77.
With I. Mena, F. C. Brown, P. S. Papavasiliou, and S. T. Miller.
Defective release of growth hormone in Parkinsonism improved
by levodopa. N. Engl. J. Med. 288:320-21.
With P. S. Papavasiliou, I. Mena, and M. Bell. Oxybate sodium for
Parkinsonism. JAMA 224:130.

1974
Levodopa, manganese and degenerations of the brain. In The Harvey
Lectures, series 68, pp. 115-47. New York: Academic Press.
With P. S. Papavasiliou and I. Mena. Short and long-term approaches
to the “on and off” phenomenon. Adv. Neurol. 5:379-86.
With P. S. Papavasiliou, I. Mena, L. C. Tang, and S. T. Miller. Man-
ganese and catecholamines. Adv. Neurol. 5:235-43.
With I. Mena, P. S. Papavasiliou, and J. Mendez. Unexpected find-
ings with apomorphine and their possible consequences. Adv.
Neurol. 5:295-99.
With I. Mena, P. S. Papavasiliou, J. Mendez, and F. C. Brown. Chronic
 GEORGE CONSTANTIN COTZIAS 81
treatment with Levodopa and growth hormone release. Adv. Neurol.
5:471-76.
With J. S. Mendez, P. S. Papavasiliou, and I. Mena. “On-off” phe-
nomenon during treatment of Parkinsonism with L-dopa. In Cur-
rent Concepts in the Treatment of Parkinsonism, ed. M. D. Yahr, pp.
151-60. New York: Raven Press.
With W. G. Clark, M. K. Menon, L. R. Hines, R. M. Hoar, S. M.
Kurtz, P. A. Mattis, I. Iwai, H. Watanabe, and J. C. Page. The
acute toxicity of l-dopa. Toxicol. Appl. Pharmacol. 28:1-7.
With S. T. Miller, A. R. Nicholson, Jr., W. H. Maston, and L. C.
Tang. Prolongation of the life-span in mice adapted to large amounts
of L-dopa. Proc. Natl. Acad. Sci. U.S.A. 71:2466-69.
With L. C. Tang and J. Z. Ginos. Monoamine oxidase and cerebral
uptake of dopaminergic drugs. Proc. Natl. Acad. Sci. U.S.A. 71:2715-
19.
With L. C. Tang and M. Dunn. Changing the actions of neuroactive
drugs by changing brain protein synthesis. Proc. Natl. Acad. Sci.
U.S.A. 71:3350-54.

1975
With J. S. Mendez, I. Mena, and P. S. Papavasiliou. Diphenylhydantoin:
blocking of levodopa effects. Arch. Neurol. 32:44-46.
With I. Mena. Protein intake and treatment of Parkinson’s disease
with levodopa. N. Engl. J. Med. 292:181-84.
With S. T. Miller and H. A. Evert. Control of tissue manganese:
initial absence and sudden emergence of excretion in the neona-
tal mouse. Am. J. Physiol. 4:1080-84.
With P. S. Papavasiliou, S. T. Miller, H. W. Kraner, R. Hsieh. Se-
quential analysis: manganese, catecholamines and L-dopa induced
dyskinesia. J. Neurochem. 25:215.
With J. S. Mendez, E. W. Finn, and K. Dahl. Rotatory behavior
induced in nigra-lesioned rats by N-propylnoraporphine,
apomorphine and levodopa. Life Sci. 16:1737-42.
With P. S. Papavasiliou, J. Z. Ginos, and E. Tolosa. Treatment of
Parkinson’s disease and allied conditions. In The Nervous System,
ed. D. B. Tower and T. N. Chase, vol. 2., pp.323-29. New York:
Raven Press.
With J. Z. Ginos, E. Tolosa, L. C. Tang, and A. LoMonte. Cholin-
ergic effects of molecular segments of apomorphine and dopa-
82 BIOGRAPHICAL MEMOIRS

minergic effects of N, N-dialkylated dopamines. J. Med. Chem.

18:1194-1200.
With P. S. Papavasiliou, E. S. Tolosa, J. S. Mendez, and M. Bell-
Midura. The treatment of Parkinson’s disease with aporphines:
possible role of growth hormone. N. Engl. J. Med. 294:567-72.

1976
With L. C. Tang. Modification of the actions of some neuroactive
drugs by growth hormone. Arch. Neurol. 33:131-34.

1978
With P. S. Papavasiliou, V. F. L. Rosal, and S. T. Miller. Treatment
of Parkinsonism with N-n-propyl norapomorphine and levodopa
(with or without carbidopa). Arch. Neurol. 35:787-91.
GEORGE CONSTANTIN COTZIAS 83